This is a revised application to enable renewal of the Southern Community Cohort Study (SCCS). It has long been known that rates of cancer incidence and mortality are elevated among African Americans. The SCCS is a landmark prospective investigation into the determinants of these disparities. Over the past 5 years, by partnering with Community Health Centers (CHCs), facilities providing basic health care mainly to the uninsured, across 12 southern states, we have overcome barriers that have traditionally restricted participation of African Americans in health studies. The first renewal of the SCCS, proposed herein, will enable completion of enrollment so that the cohort will include approximately 90,000 men and women, nearly 70% African American, age 40-79. The new enrollees will be recruited from CHCs and complete an in- person interview about medical, lifestyle and other characteristics, with >90% expected to provide biologic specimens (blood, buccal cells, and/or urine). Follow up of the entire cohort to identify deaths and incident cancers and update exposure profiles will be carried out. We describe in the revised application enhanced approaches to active follow up, as requested by the initial reviewers, and indicate how they have already improved response rates in our pilot follow up study. Longitudinal analyses and nested case-cohort studies utilizing the interview data and biologic specimens will be initiated during the renewal period to evaluate specific hypotheses about cancer among African Americans which can uniquely or with special advantage be assessed within the SCCS. The hypotheses are related to energy balance (weight gain, obesity and physical inactivity), vitamin D, inflammation, selenium and other nutrient intakes, tobacco metabolism, and cancer screening practices and their impact on incidence and/or mortality of the major cancers (lung, prostate, breast, and colon/rectum). Initial SCCS data show sometimes marked racial differences in these variables. The cohort possesses attributes, such as a 44% prevalence of obesity (reaching 57% among Black women) and a 44% prevalence of current smoking which place it at exceptionally high risk of cancer. The SCCS is thus unique among all cohorts and comprises a population of urban and rural blacks and whites, often of low income, seldom if ever included in previous studies. The renewal will enable the SCCS to be a national resource, with comprehensive biologic and questionnaire data available for assessing, both within the SCCS and in combination with other molecular epidemiology consortia, the etiology of cancer and reasons for the largely unexplained higher rates among blacks. The ultimate public health benefit will be Progress towards the development of measures aimed at cancer prevention, the elimination of cancer inequalities and the reduction of the cancer burden among all groups.